Multivariate spectral analysis and monitoring for biomanufacturing

Abstract

The disclosure features methods that include obtaining a vibrational spectrum of a solution in a biological manufacturing system, analyzing the vibrational spectrum using a first chemometrics model to determine a value of a first quality attribute associated with the solution, analyzing the vibrational spectrum using a second chemometrics model to determine a value of a second quality attribute associated with the solution, and adjusting at least one parameter of a purification unit of the biological manufacturing system based on at least one of the values of the first and second quality attributes.

What is claimed is: 
     
       1. A biological manufacturing system, comprising:
 a radiation source configured to generate radiation; 
 a detection apparatus comprising:
 an optical fiber comprising two fiber cores in a common cladding; 
 an optical element integrated into an end of the optical fiber so that at least a portion of the optical element is located within the common cladding, and positioned so that the generated radiation propagating through a first fiber core of the two fiber cores is incident on a first side of a surface of the optical element, wherein a flowing solution is located on a second side of the surface of the optical element opposite the first side, and radiation that undergoes total internal reflection from the surface of the optical element and does not propagate through the flowing solution is coupled into a second fiber core of the two fiber cores; and 
 a detector positioned to receive the radiation that undergoes total internal reflection from the second fiber core; and 
 
 a system controller connected to the detection apparatus, and configured to:
 receive a measurement signal from the detection apparatus corresponding to an infrared vibrational spectrum of the solution; 
 analyze the infrared vibrational spectrum using a first chemometrics model to determine value of a first quality attribute associated with the solution; 
 analyze the infrared vibrational spectrum using a second chemometrics model to determine a value of a second quality attribute associated with the solution; and 
 adjust at least one parameter of the biological manufacturing system based on at least one of the values of the first and second quality attributes. 
 
 
     
     
       2. The system of  claim 1 , wherein the biological manufacturing system is configured to produce the solution, and the flowing solution is derived from a bioreactor or the flowing solution is received from a purification unit of the biological manufacturing system. 
     
     
       3. The system of  claim 1 , wherein the flowing solution comprises a biological product comprising at least one of a protein-based therapeutic substance, a nucleic acid-based drug substance, and a gene therapy drug substance. 
     
     
       4. The system of  claim 1 , wherein the first and second quality attributes are each independently selected from the group consisting of product quality attributes, product-related impurities, and process-related impurities, for a biological product produced by the biological manufacturing system. 
     
     
       5. The system of  claim 2 , further comprising a flow cell positioned to receive the solution derived from a bioreactor of the biological manufacturing system, wherein the optical element is further integrated with a portion of the flow cell. 
     
     
       6. The system of  claim 1 , wherein the first chemometrics model comprises a first set of at least three principal vibrational components correlated with the first quality attribute. 
     
     
       7. The system of  claim 6 , wherein the second chemometrics model comprises a second set of at least three principal vibrational components correlated with the second quality attribute, and wherein the first and second sets of principal vibrational components have no members in common. 
     
     
       8. The system of  claim 1 , wherein adjusting the at least one parameter of the biological manufacturing system comprises transmitting a signal comprising instructions to adjust a pH of a solution in a bioreactor of the biological manufacturing system. 
     
     
       9. The system of  claim 1 , wherein adjusting the at least one parameter of the biological manufacturing system comprises adjusting a concentration of a species in a bioreactor of the biological manufacturing system, wherein the species comprises at least one member selected from the group consisting of lactate ions, ammonium ions, glucose, and glutamine. 
     
     
       10. The system of  claim 1 , wherein adjusting the at least one parameter of the biological manufacturing system comprises adjusting a cell density in a bioreactor of the biological manufacturing system. 
     
     
       11. The system of  claim 1 , wherein the first and second fiber cores are coupled to different surfaces of the optical element. 
     
     
       12. The system of  claim 1 , wherein the optical element comprises an incident surface through the generated radiation enters the optical element from the first fiber core, and wherein the incident surface is oriented non-orthogonally with respect to an axis of the optical fiber. 
     
     
       13. A biological manufacturing system, comprising:
 a first purification unit configured to purify a solution comprising a biological product; 
 a second purification unit configured to receive the solution from the first purification unit; 
 a flow cell positioned so that the solution passes through the flow cell between the first and second purification units; 
 a radiation source configured to generate radiation; 
 a detection apparatus comprising:
 an optical fiber comprising two fiber cores in a common cladding; 
 an optical element integrated into an end of the optical fiber so that at least a portion of the optical element is located within the common cladding, and positioned so that the generated radiation propagating through a first fiber core of the two fiber cores is incident on a first side of a surface of the optical element, wherein the solution is located on a second side of the surface of the optical element opposite the first side, and radiation that undergoes total internal reflection from the surface of the optical element and does not propagate through the flowing solution is coupled into a second fiber core of the two fiber cores; and 
 a detector positioned to receive the radiation that undergoes total internal reflection from the second fiber core; and 
 
 a system controller connected to the detection apparatus, and configured to:
 receive a measurement signal from the detection apparatus corresponding to an infrared vibrational spectrum of the solution; 
 analyze the infrared vibrational spectrum using a first chemometrics model to determine value of a first quality attribute associated with the solution; 
 analyze the infrared vibrational spectrum using a second chemometrics model to determine a value of a second quality attribute associated with the solution; and 
 adjust at least one parameter of the first purification unit based on at least one of the values of the first and second quality attributes. 
 
 
     
     
       14. The system of  claim 13 , wherein the biological product comprises at least one of a protein-based therapeutic substance, a nucleic acid-based drug substance, and a gene therapy drug substance. 
     
     
       15. The system of  claim 13 , wherein the first and second quality attributes are each independently selected from the group consisting of product quality attributes, product-related impurities, and process-related impurities, for a biological product produced by the biological manufacturing system. 
     
     
       16. The system of  claim 13 , wherein the optical element is further integrated with a portion of the flow cell. 
     
     
       17. The system of  claim 13 , wherein the first chemometrics model comprises a first set of at least three principal vibrational components correlated with the first quality attribute, and the controller is configured to analyze the vibrational spectrum using the first chemometrics model by calculating the first quality attribute value based on the first set of principal vibrational components. 
     
     
       18. The system of  claim 17 , wherein the second chemometrics model comprises a second set of at least three principal vibrational components correlated with the second quality attribute, and wherein the first and second sets of principal vibrational components have no members in common. 
     
     
       19. The system of  claim 13 , wherein adjusting the at least one parameter comprises selectively directing one eluent stream from among multiple eluent streams into the second purification unit from the first purification unit. 
     
     
       20. The system of  claim 13 , wherein adjusting the at least one parameter comprises at least one member selected from the group consisting of adjusting a pH of the solution in the first purification unit, and adjusting a buffer composition of the solution in the first purification unit. 
     
     
       21. The system of  claim 13 , wherein adjusting the least one parameter comprises adjusting a retention time of the solution in the first purification unit. 
     
     
       22. The system of  claim 13 , wherein the first and second fiber cores are coupled to different surfaces of the optical element. 
     
     
       23. The system of  claim 13 , wherein the optical element comprises an incident surface through the generated radiation enters the optical element from the first fiber core, and wherein the incident surface is oriented non-orthogonally with respect to an axis of the optical fiber.